Despite the literature focusing on the considerable challenges with injectable depots for biomacromolecules, hydrophobic compounds are an extremely significant class of drug substances and pose unique challenges in their own right. It is estimated that up to 40% of all new chemical entities show poor solubility. The term “hydrophobic compound” roughly describes a heterogeneous group of small molecules (less than 1300) that exhibit poor solubility in water but that are typically, but certainly not always, soluble in various organic solvents. Often, the terms slightly soluble (1-10 mg/ml), very slightly soluble (0.1-1 mg/ml), and practically insoluble (<0.1 mg/ml) are used to categorize such compounds. Additionally “basic compound” means that when the compound is dissolved in water it gives a solution with hydrogen ion activity greater than that of pure water and a pH of more than 7.0. The basic compound may also be a hydrophobic compound.
Controlled-release dosage forms improve the effectiveness of drug therapy by increasing the therapeutic activity while reducing the intensity of side effects and number of drug administration required during treatment. For certain drugs that (i) have a broad therapeutic window, (ii) require a low daily dose, and (iii) are going to be used for the long-term treatment of disease, injectable controlled release depots such as drug-loaded biodegradable polymer microparticles, may provide such an alternative delivery strategy, potentially rescuing an otherwise undeliverable drug.
Biodegradable microparticles (microcapsules and microspheres) ranging in diameter from about 10 to 125 μm can serve satisfactorily as prolonged-release drug-delivery systems. Microparticles comprised of certain therapeutic agents and suitable biodegradable matrices may be suspended in a viscous diluent and injected intramuscularly (IM) or subcutaneously.
A variety of biodegradable polymers have been used for the controlled release of different drugs. The selection and design of a suitable biodegradable polymer is the first challenging step for the development of a parenteral drug delivery system. Several classes of synthetic polymers have been proposed, which include poly(ester)s, poly(anhydride)s, poly (carbonate)s, poly(amino acid)s, poly(amide)s, poly(urethane)s, poly(ortho-ester)s, poly(iminocarbonate)s, and poly(phosphazene)s.
A variety of methods is known by which hydrophobic compounds can be encapsulated in the form of microparticles(Christian Wischke and Steven P. Schwendeman, “Principles of encapsulating hydrophobic compounds in PLA/PLGA microparticles”, International Journal of Pharmaceutics 364 (2008) 298-327). The most well-established are summarized below:
o/w Emulsion Technique (Solvent Evaporation and/or Extraction)
As a considerable number of hydrophobic compounds are soluble in various water-immiscible organic solvents and, of course, are poorly soluble in water, one of the simplest methods to encapsulate such drugs in biodegradable polymers is by the oil-in-water (o/w) emulsion/solvent evaporation and or extraction technique. The o/w process involves dissolving the polymer (in the most of the cases PLGA) in a water immiscible, volatile organic solvent (such as dichloromethane (DCM), tetrahydrofuran (THF) and ethyl acetate) and then dissolving the compound in the prepared solution or alternative dissolving the compound in a miscible co-solvent and mixing. Co-solvents are generally used for drugs that do not show a high solubility in the primary organic solvent. The resulting organic oil phase is then emulsified in an aqueous solution (continuous phase) containing an appropriate emulsifier. The emulsifiers included in the aqueous phase act as stabilizers for the oil-in-water emulsion. The emulsion is then subjected to solvent removal by either evaporation or extraction process to solidify the oil droplets. In general, volatile solvents can be removed from such emulsions by evaporation to a gas phase or in any case by extraction to the continuous phase. In the former case, the emulsion is maintained at reduced pressure or at atmospheric pressure and the stir rate is reduced while the temperature is increased to enable the volatile solvent to evaporate. In the latter case, the emulsion is transferred to a large quantity of water (with or without surfactant) or other quench medium, into which the solvent associated with the oil droplets is diffused out. Combination of solvent evaporation and extraction is also applicable. The solid microspheres so obtained are then washed and collected by sieving. These are then dried under appropriate condition such as vacuum drying or lyophilized.
s/o/w Emulsion Technique
This technique is usually used when drug cannot be dissolved in a carrier solvent or solvent mixture or extensive drug loss to the continuous phase cannot be avoided when employing cosolvent systems. In this method the drug substance is dispersed in the oil phase consisting of the organic solvent or mixture of solvents and the polymer dissolved into this phase. Due to a low but distinct solubility of certain active agents in the organic solvent, a certain portion of the drug might also be in solution in s/o/w formulations. The s/o/w method requires a very low drug particle size in order to allow a complete encapsulation of the drug crystals. Besides the necessity of small-sized drug material, other drawbacks of the s/o/w technique might be the tendency of the drug to show sedimentation (higher density than suspension medium) or flotation (caused by adhesion of gas bubbles to the hydrophobic surface due to low wettability) during the encapsulation process and, in the later stages of the product development, difficulties can also be expected during scaling up to large-scale manufacture. Alterations, which might result from changes in the drug synthesis, e.g., in the drug crystal structure or the wetting behavior, are expected to affect the release profile from s/o/w particles. Moreover, differences in the release might appear compared to dense microspheres that were prepared by the o/w technique and show a homogeneous drug distribution.
o/o Method
Although being classified as hydrophobic compounds, some active substances exhibit an appreciable solubility in aqueous media like the external water phases. Therefore, o/w methods are expected to result in low encapsulation efficiencies due to a flux of the active agent from the dispersed phase to the larger volume of the continuous phase during the encapsulation process. In order to overcome this issue, o1/o2 emulsion methods can be used. The drug substance and the polymer are dissolved in an organic solvent (e.g., acetonitrile) and then the solution is emulsified into a continuous phase consisting of a solution of an emulsifier (HLB typically <8) in oil, e.g., cottonseed oil or mineral oil. The o1-phase solvent (i.e., acetonitrile) is extracted in the external oil phase (acetonitrile solubility in cottonseed oil 10%) which should be a non-solvent for both the polymer and the drug. Alternative methods concern the s/o/o technique combining the concepts of s/o/w and o/o methodologies. However, for methods carried out in oil the removal of the continuous phase requires a special treatment, e.g., washing of the particles with hexane or petroleum ether. The emulsification process can be achieved by the mechanical stirring, high shear mixers and/or static mixers.
Spray Drying
Microparticles are obtained by spraying a solution or suspension of a drug in an organic solution of the polymer. Spray drying is defined as the transformation of a feed from a fluid state (solution, or dispersion) into a dried particulate form by spraying the feed into a hot gaseous drying medium (e.g., hot air). It is a continuous one-step processing operation in which four different phases can be distinguished, namely: atomization of the feed, mixing of spray and air, solvent evaporation, and product separation. A variety of atomization systems are available, which may be classified according to the nozzle design as rotary atomization, pressure atomization, and two-fluid atomization. Spray drying technique can overcome the issue of large volumes of solvent-contaminated water phase that result from emulsion-based encapsulation methods, however it faces scalability issues related to technology transfer from small to large scale production.
There is a substantial body of evidence supporting the hypothesis that the release of drug from sustained release parenteral systems is predominately controlled by the characteristics of the delivery system and dependent mainly on a combination of diffusion (early phase) and hydrolytic erosion (later phase) (Cheng-ju Kim, Controlled Release Dosage Form Design, TECHNOMIC publications; Xiaoling Li, Bhaskara R. Jasti, Design of Controlled Release Drug Delivery Systems, McGraw-Hill). Release profiles are typically illustrated as the cumulative release, expressed as a percentage of the total amount of active agent present in the microparticles, as a function of time. Different clinical applications, and/or different active agents, may require different types of release profiles. For example, one type of release profile includes a substantially linear release profile over time. Another type of release profile is a sigmoidal release profile characterized by an initial lag phase, a steep intermediate release phase, and a flat final release phase.
The drug release mechanism form PLGA microparticles has been found to be a combination of polymer erosion and drug diffusion (N. Faisant et al., “PLGA-based microparticles: elucidation of mechanism and a new, simple mathematical model quantifying drug release”, Eur. J. Pharm. Aci., 15 (2002) 355-366). One critical variable that affects the release profile of the biodegradable microparticle product is the molecular weight of the polymer or polymeric matrix material in the final microparticle product. The molecular weight of a polymer influences the biodegradation rate of the polymer. For a diffusional mechanism of active agent release (diffusion-controlled), the polymer should remain intact until the entire active agent is released from the microparticles, and then degrade. The active agent can also be released from the microparticles as the polymeric matrix material bioerodes (degradation-controlled). By an appropriate selection of polymeric materials a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties.
Drug release from biodegradable PLGA microparticles of particle size >10 μm is controlled by matrix/bulk-erosion and these systems are selected when sigmoidal release profiles are required (M. Körber, “PLGA Erosion: Solubility- or Diffusion-Controlled?”, Pharm Res (2010) 27:2414-2420). The polymer chain of water-insoluble polymer is broken down to smaller, water soluble molecules by hydrolysis of labile ester bonds in the polymer backbone. Then drug dispersed physically in the interstices of the polymer matrix releases. The by-products of the polymer degradation are lactic and glycolic acids, which are commonly found in metabolic cycles in the body. The drug release is expected to begin after a lag time when the polymer Mw falls below a critical value where mass loss can take place. Different polymer types are known to require different times for complete degradation, with larger molecular weight and particularly higher lactide content, and, in the case of l- or d-PLA, crystalline instead of amorphous structures, resulting in a slower degradation and an expected slower release. In general, drug release from a matrix-controlled system does not furnish zero-order kinetics unless intricate fabrication processes used in manufacturing (e.g. ununiformed concentration distribution, modification of geometry, etc).
Unexpected early and/or almost linear release profiles form PLGA microparticles have been observed for basic/nucleophilic drug substances (e.g., compound carrying tertiary amino groups) (H. V. Maulding et al., “Biodegradable microcapsules: acceleration of polymeric excipient hydrolytic rate by incorporation of a basic medicament”, Journal of Controlled Release 3 (1986) 103-117; Y. Chsn and C. G. Pitt, “The acceleration of degradation-controlled drug delivery form polyester microspheres”, Journal of Controlled Release 8 (1989) 259-265;). The very rapid drug release (observed both in vitro and in vivo) is attributed to the acceleration of the hydrolytic degradation of the polymer matrix (hydrolytic cleavage of the polymer chain ester bonds) caused by the basic drug substances (base catalyzed hydrolysis). Examples of such drug substances that induce the hydrolysis of the PLGA polymers include but not limited to thioridazine hydrochloride, ketotifen, cinnarizine, indenorol, clonidine, naltrexone, merepidine, methadone, promethazine and risperidone. It was proved that the steric accessibility of the unsolvated amine nitrogen of the compound defined its catalytic effectiveness and the degree of acceleration of polymer chain scission was proportional to the initial concentration of the base (% drug loading) into the polymer matrix. In particular, thioridazine HCl was incorporated into PLGA microspheres resulting in almost immediate release occurring both in vitro and in vivo contrary to the results expected with a polymer as PLGA which degrades in about one year and releases drugs over weeks to months. Another amine, ketotifen, was employed in making microspheres with PLGA and analogous in vitro release results were observed. Accelerated degradation rates related to rapid release were also observed for microparticles containing meredipine, methadone and promethazine.
Another active compound inducing hydrolysis of polyesters backbones such as PLGA polymers is Risperidone. Risperidone (also known as 4-[2-[4-(6-fluorobenzo[dJisoxazol-3-yl)-I-piperidyl]ethyl]-3-methyl-2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-one and marketed under the trade name RISPERDAL®) is an atypical antipsychotic medication indicated for the treatment of schizophrenia. Risperidone product is also available in the market as sustained release parenteral depot under the trade name RISPERDAL CONSTA. Risperdal consta product consists of a vial containing the microspheres for depot suspension and a pre-filled syringe containing a suitable solvent for suspension. The solid powder of microparticles is mixed with diluent to become a suspension that is given every-two week intramuscularly. The in vivo release profile of Risperdal consta is as follows: classical tri-phasic release pattern with a low burst effect (≤3.5%), a latent period of 4 weeks with no release, and the preponderant drug release between weeks 4-6.
Degradation studies of PLGA microparticles containing risperidone compared to placebo microparticles (without risperidone) revealed that the presence of risperidone accelerates the degradation rate of PLGA polymers (F. Selmin, P. Blasi and P. P. DeLuca, “Accelerated Polymer Biodegradation of Risperidone Poly(D, L-Lactide-Co-Glycolide) Microspheres, AAPS PharmSciTech, Vol. 13, No. 4 (2012) 1465-1472). The hydrolytic effect of risperidone was also observed during the preparation of microparticles when risperidone and PLGA polymer are co-dissolved in organic solvent to prepare oil phase to be emulsified in the aqueous continuous phase. Patent EP1282404 provides a method for the control of the molecular weight of a polymer forming microparticles containing a nucleophilic compound by adjusting hold time and temperature of the nucleophilic compound/polymer solution during the manufacturing process. The acceleration of the polymeric matrix of microparticles by the presence of risperidone substance results in rapid drug release and often in undesired linear release profiles.
Thus, there is a need in the art for an improved method for controlling the release profile in the finished microparticle product containing basic/nucleophilic compounds such as risperidone. Alternatively the present invention is also suitable for hydrophobic compounds that have poor water-solubility and a high drug loading of >20% w/w is required. Patent EP-B-1140029 claims a method for the preparation of PLGA microparticles containing risperidone with “s”-shaped release profile by adjusting the degree of drying that is performed during the preparation of the microparticles. In particular, the patent discloses that additional intermediate drying steps of the particles can provide sigmoidal release profile. This method however increases the number of the processing steps and complicates manufacturing and increase risks when microparticle products are intended for human use and production should take place under aseptic conditions.